With the worms - a chapter from the book "The Common Thread - The Human Genome"

The book was recently published by Aliyat HaGeg Books and Yediot Books

introduction

This is the story of an extraordinary enterprise, one of the outstanding achievements of science at the end of the twentieth century, the sequencing of the human genome. The story is told again and again over the pages of the popular press, often accompanied by breath-taking headlines and bold claims about the end of every epidemic and disease. And as if all this wasn't exciting enough, the story became even more exciting when a competitor entered the fray and thus turned a scientific investigation into a "race".

So why tell this story again? It seems to us that only an inside look can give a reliable picture of the dramatic developments in the last decade, which were too complicated and complex to be summed up in the - convenient but misleading - metaphor of a "race" to the genome. As the head of the largest genome sequencing research center outside of the United States, John is in a unique position, allowing for a probing and incisive view of the politics behind a scientific development that was equally important to corporate capital and human health. Sequencing the human genome is the latest step in a process that began in the XNUMXs, when two fields of research began to merge together. One was human genetics: the study of heredity patterns, the ability to discover genetic causes of disease; The second was molecular biology, which studies the material from which genes are made: DNA, the molecule that makes life possible. DNA encodes the instructions for creating every living thing as a sequence of genes - using a simple four-letter alphabet.

In 1990, an international publicly funded effort, the Human Genome Project, began with the goal of sequencing and mapping human DNA and making the information contained therein available and free to the scientific community. Much to the confusion, people sometimes talk casually about "mapping" the human genome when they actually mean "the floor". The difference is, in part, a question of size - you can make a useful map to help you find genes without knowing the full sequence of letters (three billion, in the case of the human genome). But although the sequence is indeed the ultimate map, it is also much more than that: it is the biological information itself. When we finish deciphering the sequence, we will have the hieroglyph of biology in our hands, even if we don't understand it all at the very beginning.

Deciphering the information will take a long time and will require every free mind to work. It is equally essential that the sequence be available to the entire biological community. No single person or group can credibly claim that they alone possess the expertise required to do so. When the commercial company, which later became Celera Genomics, was founded in May 1998 with the stated goal of being "the sole source for the genome and related medical information", the entire future of biology was in jeopardy. This is because one company tried to gain a monopoly on access to the most basic information about humanity, information that is - or should be - a common heritage for all.

To their great credit, it must be said, the public bodies that financed the human genome project decided not to abandon the campaign in favor of Celera, but to make the sequence available to everyone even faster, even if temporarily it will be at a lower level of accuracy and completeness than originally planned. Thus the world celebrated with fanfare the completion of the "working draft" of the sequence in June 2000; Although it will be several more years before the floor centers finish the job, today any scientist anywhere in the world can access the sequence freely and free of charge, and also use the information to continue their discoveries. We wrote this book so people could understand how close the world came to losing that freedom.

Secretly and unwittingly, the ethos that dominates the world of science has changed in recent decades. What was once a joint enterprise, where discoverers were recognized for their discoveries but the results of their research were freely distributed, today is often bound by the demands of commercial competition. Driven by financial gain, constrained by sponsorship deals, or simply out of self-preservation, many researchers trade their discoveries with the rest of the community only under the protection of patent laws or trade secrets. On the other hand, there are still many researchers who cling to the old ideals of science. These raised their voices in protest at the way things are going. The Human Genome Project provides an example of the choices faced by individual scientists and society as a whole. We hope that this story contains the sheer excitement of scientific discovery, but also provokes thought regarding the enormous responsibility placed on those who hold the secrets of the human race.

A word or two about the "voice" in which the book is written. We wrote it together, in full partnership as much as possible. But we agreed from the beginning that since we are telling John's story, the story should be in the first person - in his own voice. The main source was John's memory, backed up by his email files, which actually constituted a daily record of the project. In addition, we interviewed many of the other main characters; Their perspectives were invaluable in filling in missing details and verifying John's recollections. The result, to the best of our ability, is an extremely accurate account of what really happened.

John Selston and Georgina Perry

Prologue: Siewset

"I heard the prison door slam behind us."

I was standing with Bob Waterstone on the bright white platform of a small train station in Syracuse, on the Long Island Railroad, and we were waiting for the train to New York. The sun was bright and blazing. We were on our way home from the 1989 Nematode Biology Conference in Cold Spring Harbor. It was always difficult for me to go to the worm meetings - to leave behind the wonderful softness of an English spring and travel to this land of sharp shadows and strong contrasts. Today I feel that the transition is less sharp than before, but the difference is always there.

The Worm meetings have been held once every two years since 1977, but that meeting was special. Alan Coulson spread the long scrolls, on which he mapped and sketched the worm's genome, across the back wall of the Bush Lecture Hall. During the entire three days of the meeting, he was besieged from all sides by people who wanted to check details and add information before they parted ways for another two-year work period on the real thing in biology - the discovery of the place, time and manner in which individual genes direct the complete functioning of the worm.

At a certain point, Jim Watson, one of the discoverers of the DNA double helix and in those days the head of the Human Genome Project, saw the map. "You can't look at it without wanting to continue it, huh?" the city Our map showed overlapping pieces of the worm's DNA, arranged in the correct order and bounded by agreed-upon placemarks. The meaning of the worm floor was to read each of the 100 million letters, or bases, in its genetic code. This will give us the ultimate map: all the information needed to create a worm. In terms of knowing and understanding the worm's genome, it would be like the difference between a school globe and a set of city maps, with every street and every house marked.

Later we sat in Jim Watson's office and discussed how exactly we could do this. We reached an agreement: Bob's labs in St. Louis and mine in Cambridge would sequence three million bases out of the 100 million bases in the worm's genome over the next three years to show that we could do it. If all goes well, we will apply for the financing to finish the rest.

This is what we could have planned. We had no way of knowing that we would soon be involved in a stormy, controversial, but ultimately successful project - a project that ultimately resulted in the announcement of the draft human genome sequence in June 2000.

On that May afternoon, as we waited in the hot sun for the train to New York, the end was still far away. No one has yet sequenced more than 250,000 bases, let alone three or 100 million. Many saw the idea as a waste of time and resources. But we have committed to do so. In the sudden silence after the commotion at the worm meeting, I was suddenly struck by the realization that there is no going back: from here one can only step forward. The sound of the prison door slamming echoed in my ears. It was one of the most exciting moments of my life.

with the worms

If there is any distinct symbol that art adopted from the field of science in the twentieth century, then it is DNA. There is a good reason for this: this molecule, as Francis Crick shouted into the ears of amused patrons at the Eagle Pub in March 1953, contains the secret of life. In most depictions of it, it is drawn as a double helix, rather short and thick, as its other remarkable feature is rarely shown: it is incredibly narrow and long. Every cell in the human body has two meters of this molecule; If we were to draw a diagram of it on a uniform scale, where its thickness was the thickness of sewing thread, then the length of the molecule would be about 200 kilometers.

Like the cotton fibers, the DNA molecules can stick together and form a visible thread, and this allows for a rather pleasant experiment. When the artist Mark Quinn (Quinn) consulted me about the DNA exhibit for his exhibition at the White Cube gallery in London in 2000, I was happy to help*. He gave me a sample of his sperm (Mark is famous for using his own bodily fluids in his work, in order to reveal and present himself; in 1991 he made a cast of his head using four and a half liters of frozen blood), and I cracked the sperm cells with detergent and a chemical Special that softens their hard coat. Sperm cells are basically compressed and packaged DNA, and the solution became very viscous as the contents of the cells were released into it. We transferred part of the solution to a tall glass test tube, and then covered the solution with a little clean alcohol. We passed a glass stick through the alcohol into the solution, stirred gently and slowly pulled the stick up and out. Tiny fibers appeared and coalesced into a thread that clung to the stick. We pulled it up until it reached the end of the test tube, then we attached the wire to the rim. Mark placed the test tube in front of a black and shiny surface, and we stood there and happily embraced the sight of this beautiful thing: Mark's DNA, a web of molecules each of which is smaller than visible to the naked eye, combined as a single, bright thread. The secret of his life.

You can do a similar experiment with any living embroidery: even if you don't have a complete laboratory at hand, you can achieve pretty good results in your home kitchen, if you use onions as a source of embroidery and dishwashing liquid, salt and vodka for distilling the DNA. It will look exactly like human DNA, and the reason for this is very simple: chemically, it is exactly the same type of molecule. DNA is the common thread that links every living being to a single ancestor.

But your DNA also makes you different from an onion, and from every other person. The DNA molecule carries a code*, where instructions are written that determine whether a fertilized egg will develop into a human or an onion. Even smaller differences in the coded instructions determine the infinite variety of hair color, complexion, body shape and personality, which makes each of us a unique individual. Each instruction - or garden - has a role in the creation of the whole, and the general result is also partly determined by the environment; But the combined power of the information in the entire genome - the complete assembly of an organism's DNA - is truly astonishing. The project that is being carried out now with the aim of harnessing and utilizing this power through reading and understanding the set of instructions that creates man - the human genome - is one of the most important enterprises in modern science. He will change our lives; The question of whether it will be good or bad depends on the answer to another question: how we will use this knowledge.

Everyone seems to understand this, judging by the media frenzy that accompanied the June 2000 announcement of the completion of the draft human genome. But despite the returns, the work is far from complete. The reading process will be mostly completed in the next few years, but the decoding and understanding will take many more years, and will encompass all life sciences. The generation that will truly understand the human genome - or the onion genome, for that matter - will understand life itself.

I never really intended to enter the multi-aspect circus of the Human Genome Project. Just ten years ago, I would have burst out laughing if someone had said that I would soon manage a research center with a staff of nearly 500 people, dive into the politics of an international project and take part in a verbal war in the media. All I wanted to do was read the genetic code of the capillary worm. I had no idea that the worm was going to lead us straight to the human genome. Of course, reading the DNA of a worm is good preparation for reading the DNA of any other species, including humans; But when we started reading the worm genome we didn't think about other species at all. We simply wanted to complete the background to the increasingly complex picture of the biology of this tiny creature; An image that developed over the 25 years that preceded it.

My first encounter with the worm was in 1969, when I arrived at the Molecular Biology Laboratory of the Medical Research Council in Cambridge - better known as LMB - to work as a staff member in Sidney Brenner's research group. Sidney was co-director, along with Francis Crick, of the cell biology division at the laboratory. Externally, they were a perfect contrast - Francis was tall, with sand-colored hair, while Sidney was short and dark-skinned, with deep-set eyes penetrating under bushy eyebrows - but both were great talkers. Having been born and educated in South Africa, Sidney arrived at Oxford as a student in 1952, with a medical degree but determined to work on gene biology. He quickly established his position among the international group of scientists who worked on the genetics of bacteriophages - tiny viruses that harm bacteria. It was these scientists who laid the foundations of modern molecular biology.

In 1953, Francis Crick and Jim Watson discovered the double helix structure of DNA, and Sidney was among the first to visit Cambridge and hear about the discovery first hand. He moved to live permanently in Cambridge in 1957, and worked with Francis on deciphering the genetic code and understanding the way in which the cells translate it into the protein molecules necessary for their various functions. In the mid-sixties, Sidney thought that the preoccupation with the question of how genes produce proteins was almost over, and asked to move to the next stage. His plan was extremely ambitious: to understand how an entire animal is coded through its DNA. Naturally he wanted to start with something simple, and the animal he chose was the capillary worm. "We intend to identify every cell in the worm and trace cell lineages*," Sidney wrote in his request for support for the project. "We will also investigate the consistency of embryonic development and the genetic control of development by searching for mutants." Sidney later recalled that some people thought it was a completely ludicrous idea. "Jim Watson said at the time he wouldn't have given me a penny to do it," he said. "He claimed that I was 20 years ahead of my time."

Why did Sidney choose a worm? Biology has a long tradition of studying simple animals with the aim of discovering mechanisms that operate in all living things. When Sidney started his project, most geneticists were working with yeast or bacteria, or with the fruit fly (Drosophila melanogaster). But none of these suited his purposes. Yeast and bacteria are unicellular organisms; One of the main goals of his program was to test how the genes direct the successive divisions of cells during which they turn an egg into an adult in a multicellular animal. On the other hand, the fly, with its complex eyes, wings, jointed legs, and elaborate behavioral patterns, was too complicated to be sufficiently accessible for the kind of exhaustive analysis Sidney planned. Capillary worms, or roundworms, were not as widely studied as the creatures mentioned, but they were not unfamiliar to biology. They form a large family that includes parasitic and free species. Sidney became interested in a non-parasitic, soil-dwelling species, Caenorhabditis elegans: a long name for a tiny creature, about a millimeter long from head to tail.

In the wild, C. elegans lives in the soil and feeds voraciously on any bacteria or other microorganism it can find. It grows from an egg to an adult in three days (a third of the time needed for the fermentation fly), except when food is scarce. So she can exist for several months in a dormant form* without reproduction. Most adults are bisexual and produce several hundred offspring through self-fertilization. Males appear from time to time in the ratio of one to several hundred, and mating allows for genetic mixing. Such mixing is essential if the species is to continue its development. The anatomy of the worm is quite simple, but even though it lacks many of the physiological characteristics of more developed animals - such as a heart, lungs and bones - it can still perform many simple actions: movement, eating, breeding, sensing the environment and so on. It basically consists of two tubes, one inside the other. The outer tube includes the skin, muscles, excretory systems, and most of the nervous system; The inner tube is the intestine. The worm moves by alternately contracting its back and abdominal muscles, twisting its body into a series of S-shaped twists.

Furthermore: the worm is very suitable for the type of research Sidney conceived. It is easy to keep and grow in the laboratory, when it exists freely in Petri dishes lined with a substrate of bacteria of the species Escherichia coli [used as food for worms]. It is even possible to leave the worm in the state of a suspended animal in the freezer for years - something that allows you to preserve a stock of different varieties of the animal. Both larvae and adults are transparent, so with a suitable microscope you can see not only their internal organs but also their cells. The bisexual adult normally has exactly 959 cells, apart from the egg and sperm cells. (For comparison: the fruit fly has a larger number of cells in each of its eyes, and the human body has 100 trillion cells). The worm's genome consists of 100 million bases, divided between six segments or chromosomes.

Sidney hoped to be able to find direct links between the worm's genes and its development from a fertilized egg to an adult, as a direct continuation of the classic research path of geneticists, which had been in use since the first decades of the twentieth century. In any biological species that reproduces rapidly - such as the worm or the fruit fly - random changes occur in the DNA that cause the animal to look or behave in an unusual way. These changes are known as mutations, and the animals that have been changed are called mutants. Geneticists quickly developed a variety of methods to increase the normal mutation rate. In the sixties there was no way to analyze the DNA directly, but by cross-hybridizing mutants and observing the inheritance patterns of later generations it was possible to map the relative position on the chromosome of the mutated genes. It is likely that mutations that tend to be inherited together will be close together on the chromosome; Those who do not see any connection between them, are likely to be on different chromosomes. Along with gene mapping, Sidney hoped that through careful microscopy and biochemistry, he could discover what exactly was wrong with mutant worms at the cellular level.

At the beginning of his career, with the help of young researchers - most of them American - Sidney was very successful in finding mutants and mapping the damaged genes along the chromosomes; To the embarrassment of the skeptics who claimed that the worm is so boring in its appearance and behavior that it will never be able to differentiate between the mutants and the normal individuals. But it turned out that the period of time required for the entire project was longer than Sidney expected. Genes almost always work as an orchestra and not as soloists - it is very rare to find a straight line passing from one gene to one function. Even so, the whole business developed to far greater proportions than Sidney could have predicted, as his intuition led him to an animal of tremendous research potential.

In a way typical of Sydney's style - in fact, the style of the entire LMB - I was given a space of about a meter on a table in a crowded laboratory when I arrived, and I was more or less left to fend for myself. Sidney and Francis believed that overcrowding in the laboratory encouraged people to form relationships with each other and that "wide desks encouraged wasting time." I found myself in a group of young researchers, amazed at the fact that we were being paid to do what we really wanted to do, knowing that we would have no one to blame but ourselves if we failed. I compared my notes with another who had just arrived, who was just as amazed as I was at the pride bordering on arrogance we met in the lab. "Who do these people think they are?" I remember saying. But gradually we realized that they had a right to be proud, and as time passed we also adapted a little of this pride to ourselves, even though personally I was convinced that I would never be able to be good enough to justify the past glory of the LMB.

The laboratory was and still is one of the most important centers for the study of the molecular basis of life. More than anywhere else, it was where molecular biology was invented. His unique ethos undoubtedly played an important role in shaping my development as a scientist. It grew out of a fortunate combination of circumstances in the years after World War II. Many scientists from the academy were involved in research related to the war, and the results were spectacular: radar, high-speed computing, antibiotics and nuclear technology - all of these had their origins in research done during the war. It became clear to the government in those days that investing in science can yield long-term results. Until the late XNUMXs there were not many opportunities to do scientific research in Britain unless you had a university teaching appointment or a private income. But ten years later, it suddenly became easy to receive generous grants from bodies budgeted by the government, such as the Medical Research Council or the Department of Scientific and Industrial Research. This sudden openness came at one of the most exciting times in the history of biology, when more and more people began to apply methods from the field of physics and chemistry to solving biological problems.

Lawrence Bragg was a physicist who headed the Cavendish Laboratory - the Physics Department of the University of Cambridge. Bragg, as a young man, was one of the pioneers of X-ray (X-ray) crystallography, which made it possible to study the three-dimensional arrangement of atoms in molecules, including biological molecules. Among his crew members was one chemist, a strict and quiet Viennese immigrant named Max Perutz. Perutz, together with a young colleague, John Kendrew (Kendrew), also a chemist, tried to decipher the structure of the blood protein hemoglobin. X-ray crystallography worked well on small molecules, but proteins contain thousands of atoms and progress was slow. Bragg, a highly influential figure in the world of British science, was an enthusiastic supporter of Perutz's work. In May 1947 he wrote to the secretary of the MRC requesting funding to establish Proutz's group "on a more permanent basis". Within months, the MRC agreed to support a unit for the study of the molecular structure of biological systems, with Peroz at its head.

The unit, which later received the more fashionable name - the Molecular Biology Research Unit - initially included only Perutz and Kendro. They were soon joined by two research students, Francis Crick and Hugh Huxley - both physicists who returned to academic life after several years of military service. Two years later, with the addition of Jim Watson - then a 22-year-old American geneticist prodigy - a whole new field of possibilities opened up. Perutz says that it was Watson who made them realize that physics and chemistry alone might not provide them with all the answers.

Watson's arrival had an electrifying effect on us, because he made us look at our problems from a genetic point of view. He didn't just ask "What is the atomic structure of living matter?" But above all "what is the structure of the gene that determines this*?"

It didn't take much to convince Francis that it was more important to work on DNA, which was only then beginning to gain recognition as the material from which genes are made, than on proteins. Francis and Jim did little experimenting themselves, but they read, talked, argued, and built models. With the critical help of the X-ray image of DNA taken by Rosalind Franklin at King's College London (presented to Watson by Rosalind's colleague Maurice Wilkins), they drew a correct conclusion as to the double helix structure of the molecule, and published it in Nature In 1953**. At that time I was a school student, 11 years old, but I remember these years as a time of tremendous excitement because so much was being revealed.

DNA is a long and narrow molecule made of a chain of units called nucleotides; Each nucleotide contains one of four bases: adenine (A), guanine (G), cytosine (C) or thymine (T). Watson and Crick concluded that two strands of DNA are wrapped around each other in a double helix structure, where A is always opposite T, and C is always opposite G. They realized that this base pairing provides the mechanism by which DNA can replicate - the requirement the basis for the development of life on earth. Using an accidental-intentional formulation, which has entered the folklore of science, Watson and Crick concluded their 1,200-word article with the sentence: "It did not go unnoticed that the specific base pairing method we determined immediately points to a possible mechanism for the duplication of the hereditary material." In other words, if you have a single strand of DNA and an unlimited supply of the four nucleotides, you can make the second strand, and from that another copy of the first strand, and so on.

A month after the publication of their first article in Nature, Watson and Crick continued with another article in which they emphasized another, highly significant implication of their theory: "In a long molecule, many different combinations are possible, so it seems likely that the exact sequence of the bases is the code that carries the genetic information." They were right; And biological research was forever changed by this insight. This is the truly important result of knowing the structure of DNA: not the helical shape itself, but getting the confirmation that the system of transmitting the instructions to create life from generation to generation is digital, and not analog - like the English language, and not at all like a diagram, for example. To convey the idea of ​​an animal purring softly with whiskers and fur, an English speaker uses the three-letter word cat, the meaning of which is clear to anyone who understands the language. A diagram, on the other hand, shows a graphic representation of a cat. A cat's DNA lists the genes (the instructions for creating a cat) just like the alphabet lists words in a language. There is no graphic representation—nothing like the tiny man curled up in the head of a sperm cell that some of the early users of the microscope thought they could see.

About the book

Fifty years after the historic announcement of the discovery of the double helix structure of DNA in 1953, came an equally revolutionary announcement of the end of one of the largest and most ambitious projects in the history of science: after seven years, the draft of the human genome was completed.

Is the completion of the huge project of "slicing the human genome" really such a dramatic turning point? And if so, for whom? In the life of science? in our lives? In the life of each of our descendants?

John Selston, winner of the Nobel Prize for Medicine, leads us behind the scenes of the scientific, commercial, moral campaign, on the way to the great achievement. He reveals to us the characters, the politics, the controversies, the big money and the prestige struggles, as someone who tells about a race between good and bad.

The common thread - the human genome

Indeed, the common thread is, among other things, the story of the good people who seek not only to advance medicine towards achievements that did not occur to us until not many years ago, but also to protect us - the citizens of this new world - and to ensure that the human genome will always be open to all and that scientific research will not be conditioned in future economic profit.

The common thread is an instructive scientific story like no other, which will captivate everyone who is on the side of science and is also troubled by the consequences of the new technological world in which science is conducted: money (so much money!), the art of management, politics, and the problematic relationship between public relations and the truth.

Professor John Selston headed the British team of the Human Genome Project for seven years (2000-1993). For his contribution to the project, Selston was awarded the Nobel Prize in Medicine in 2002.

Georgina Perry is an award-winning science journalist. She published several books, including a biography of Max Perutz, one of the pioneering biologists in the XNUMXth century, also a Nobel laureate.

The Common Thread, The Human Genome: A Story of Science, Politics and Morality by John Selston and Georgina Perry, published by Aliyat HaGeg and Yediot Books, Philosophy and Science Series edited by Yehuda Meltzer, from English: Dan Tamir, scientific editing: Adi Marcuse-Hess, cover : Pini Hamo, 351 pages.

The common thread - a note on the genome of Hebrew

Since we have not only genes but also genetics, and today even genomics and who knows what else awaits us, it is clear that the foreign genome is also simply a Hebrew genome. But from the very first moment of reading this book, of course you have to decide how to navigate between the old and the familiar (the Loez), in which the innovations keep coming, and between the new, the Hebrew "shelnu": not too many years have passed since the English sequencing became a accepted word Even in the everyday language of ordinary cultured people, and not just scientists. leave her like this?

And here, already in the second line of the fascinating book in front of us, comes the announcement: "This is the story of an extraordinary enterprise, one of the outstanding achievements of science at the end of the twentieth century: sequencing the human genome". And in this asterisk, which is not a comment by the authors but by the Hebrew system, the Hebrew scientific editor adds - "Harzafa is the Hebrew term accepted as a translation for sequencing: the act of finding the sequence of the units that make up a DNA molecule".

The older readers will surely remember the optimistic days when even this molecule tried to be "Frude". And you can actually hear the hesitations of the first ones who use the Hebrew term, how they avoid not only the foreign language but also "Ritzoff", and for an obvious reason ("it's busy"!). And it is hoped that this floor will be "acceptable", that is, in continuous use even in a decade or two, when the human genome will be treated as a matter of course in nature studies in elementary school, and when every young woman and man will be able to google and then receive it in Hebrew.

There is no guarantee for this. And what we try in this book, as in our other popular science books, is to find our way in the renewed conceptual world according to the simple principle: to try and help the Hebrew reader find his way around in a friendly way, sometimes in Hebrew and sometimes in a foreign language, which today is almost always English. Such are the notes we added, and such is the special appendix added at the end of the book by the scientific editor Adi Marcuse-Hess. Let's hope this helps.

The system, Attic books